Sickle cell disease is caused by a haemoglobin mutant called haemoglobin S, hereinafter HbS. The mutation of HbS comprises the replacement of a polar residue, glutamic acid, by a hyrophobic one, valine, in the 6th position of the .beta.-chains, and this renders the HbS capable of polymerization in the desoxy form: see Pauling et al., Science 110, 543 (1949); Ingram:Nature, (London) 178, 792 (1956). In the deoxygenated state the HbS molecules aggregate in the form of elongated microtubular structures which distort the shape of the red cell to a sickle shape. The sickled cells tend to block the blood capillaries and ultimately give rise to the squelae of sickle cell disease.
There are known compounds which affect polymerization of HbS, and there must be made a clear distinction between those which are antisickling agents and those which are antigelling agents.
The antisickling agents are those which are able to pass through the cell membrane of the erythrocytes and prevent or reverse sickling; the latter are those which are adapted to prevent polymerization of deoxygenated HbS, but which do not pass the cell membrane in sufficient quantities and thus are not adapted to prevent or reverse sickling when contacted with red blood cells of a patient suffering from sickle cell disease.
In Table II there is presented a summary of the activity of known compounds, tried for use as antisickling agents, the comparison being on the basis of effective concentrations in vitro. The last item of the Table relates to compounds of the present invention.
Antigelling agents are summarized in Table III. The antigelling agents are not able to prevent sickling nor are they suited to reverse sickling when incubated with erythrocytes.
Sickling cell disease has been studied extensively, but in spite of this there does not exist a universally acceptable therapeutic agent for the treatment of this disease. During recent years attempts have been made to provide such agents. Some of these are based on the use of three types of compounds:
a. Agents which bind covalently with the haemoglobin molecule;
b. Agents which bind non-covalently to this molecule;
c. Agents affecting the cell membrane.
Some of the known antisickling agents have a rather high degree of toxicity, one of these being, for example, potassium cyanate.
According to the present invention there are provided novel active agents for use in the prevention and treatment of sickle cell crises which are both effective and non-toxic.